Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis

INTRODUCTION — Cytomegalovirus (CMV) retinitis is the most common serious ocular complication of acquired immunodeficiency syndrome (AIDS). The majority of disease is related to reactivation of latent infection. However, the introduction of potent combination antiretroviral therapy (ART) regimens in 1996 has led to changes in the incidence, natural history, management, and sequelae of CMV retinitis [1].

The clinical manifestations, pathogenesis, risk factors, and diagnosis of CMV retinitis are discussed here. The treatment of CMV retinitis and the use of antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) are reviewed separately. (See "Treatment of AIDS-related cytomegalovirus retinitis" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

CMV IN THE ERA OF POTENT COMBINATION ART — CMV retinitis was first reported as a complication of AIDS in 1982. Prior to the availability of potent combination antiretroviral therapy (ART) in 1996, CMV retinitis occurred in 21 to 44 percent of patients with AIDS, primarily in those with a CD4 T lymphocyte count below 50 cells/microL [2-4]. In early case series, patients who survived beyond six months without CMV-specific treatment became severely visually impaired or blind. The median time to progression of disease into previously uninvolved areas of the retina while on CMV-specific antiviral therapy was 47 to 104 days, mean survival after diagnosis was 6 to 10 months, and indefinite maintenance therapy was essential [1].

However, the introduction of potent combination ART has had a dramatic impact on CMV disease in the patient with HIV. CMV disease essentially occurs only in patients with advanced immunosuppression, such as those who are either not receiving or have failed to respond to ART [5].

Incidence — In the era prior to the availability of potent ART regimens, the incidence of CMV retinitis was high. As an example, in one observational study, approximately 25 percent of AIDS patients with a CD4 count <200 cells/microL developed CMV retinitis during four years of follow-up [6]. In addition, in the placebo arm of a clinical trial of oral ganciclovir prophylaxis, which enrolled AIDS patients with a CD4 count of <50 cells/microL or patients with a history of an AIDS-defining opportunistic infection and a CD4 count <100 cells/microL, the incidence of CMV retinitis was 24 percent after only 12 months of follow-up [7].

However, the incidence of CMV retinitis has decreased by 80 percent or more since modern ART regimens became available and survival after diagnosis has increased [1,8]. This trend has been described in the United States and Europe [9,10]. In an observational study was performed of 1600 AIDS patients who were seen every six months for ophthalmic examination from 1996 to 2009 [10]. The incidence rate of CMV retinitis was 0.36/100 person-years based upon 29 incident cases during 8134 person-years of follow-up [10]. The four-year incidence rate of CMV retinitis was 12 percent, a 52 percent reduction compared with historical data [6]. A more dramatic reduction in the incidence of CMV retinitis was observed by the San Francisco Department of Public Health’s active surveillance program. From 1996 to 2000 and 2001 to 2008, the incidence of CMV retinitis after an initial AIDS diagnosis decreased by 94 percent [11].

In addition to a decrease in incidence, CMV retinitis now appears to make up a smaller proportion of CMV end-organ disease cases. In a cohort of 206 ART-naïve HIV patients presenting for care with a CD4 count ≤100 cells/mcgl between 2004 and 2013 and enrolled in a prospective National Institutes for Health observational study, only 7 (28 percent) of those ultimately diagnosed with CMV end-organ disease had evidence of retinitis on ophthalmologic exam, while 17 (68 percent) had histologically confirmed CMV gastrointestinal disease occur [12]. In contrast, 100 percent of the 39 enrollees in the placebo arm of the clinical trial of oral ganciclovir prophylaxis described above, which was conducted before potent ART regimens were widely available, had evidence of retinitis on ophthalmologic exam, while only 6 (15 percent) had histologically confirmed CMV gastrointestinal disease [7]. This phenomenon may be due to the decreased incidence of CMV viremia with widespread use of ART, in turn leading to decreased incidence of CMV spread (eg, retinitis) resulting from hematogenous spread. In contrast, gastrointestinal CMV likely arises from direct infection of gut epithelial cells resulting from local CMV reactivation in sites such as the salivary glands, which occurs frequently in immunocompetent people [13]. Thus, immune reconstitution by ART may have less impact on reducing the incidence of CMV gastrointestinal disease than retinitis.

CMV retinitis continues to be a cause of blindness among patients with AIDS in low- and middle-income countries [14-18]. However, with increased availability of ART over the past decade, the prevalence of this disease has fallen [19]. Studies from Africa and Southeast Asia report a prevalence of 5.4 and 10.1 percent, respectively, among patients with CD4 counts <100 cells/microL [18,20]. In another report from Mozambique, CMV retinitis prevalence was 9.7 percent; six of the eight patients with active disease were failing ART, suggesting that CMV retinitis should be suspected in patients failing ART as well as in ART-naïve patients with low CD4 counts [21]. Lack of diagnostic capacity continues to be the central problem in management of this disease, with still no cases reported in the literature in several sub-Saharan countries, such as Kenya, Zambia, Zimbabwe, Eswatini, and Lesotho, all of which have >5 percent HIV prevalence among young adults.

Effect on clinical presentation — The initiation of ART with associated immune reconstitution may also lead to different clinical presentations of symptomatic CMV disease:

●Patients may present with CMV retinitis in the setting of higher CD4 counts (>100 cells/microL) secondary to early immunologic recovery of T-cells after initiation of ART [22]. This emphasizes the fact that early immune reconstitution is "incomplete" and the patient is still at risk for opportunistic infections early during treatment [23]. Thus, clinicians should not eliminate the possibility of CMV retinitis simply based on a relatively high CD4 count.

●Some patients who have quiescent CMV retinitis (or subclinical CMV retinal infection) at the time potent antiretroviral therapy is initiated, subsequently develop new areas of retinal opacification within the first months after responding to antiretroviral treatment with a rise in their absolute CD4+ T cell counts [22]. These new retinal lesions are either located on the border of previous healed lesions or may be the initial clinical presentation of CMV retinitis. In patients already on maintenance anti-CMV therapy, this new retinal opacification does not signify a failure of the anti-CMV therapy or antiretroviral therapy, and the lesions subsequently heal with continuation of the same anti-CMV regimen.

Morbidity and mortality — The introduction of potent ART was also associated with decreased morbidity and mortality related to ocular involvement, slower rates of retinal progression, ocular complications, and improved survival after diagnosis [24-26].

●In the era before potent combination ART, the rates of visual loss in eyes were substantial. The two major causes were retinitis, involving either the macula or the optic nerve, and retinal detachment. In the modern ART era, visual outcomes improved significantly [27], and the overall rate of progression of retinitis is significantly slower than before [28]. However, patients with CMV retinitis who initiate ART are at risk of developing an ocular inflammatory syndrome, termed immune recovery uveitis, which can cause substantial vision loss [29]. (See 'CMV immune recovery uveitis' below.)

●Use of ART has also been associated with a decreased incidence of CMV retinitis in the uninvolved second eye [30]. In a study of 376 consecutive patients with AIDS and unilateral CMV retinitis, subjects were followed for the development of second-eye retinitis. The use of ART was associated with a 46 percent reduction in incidence of retinitis in the uninvolved eye compared to untreated patients. Rates of retinal detachment have also been reduced compared to historical controls [31].

●In a large observational cohort of 1583 AIDS patients who were enrolled between 1998 and 2003, mortality rates among patients with a baseline CD4 count >100 cells/microL were similar in those with or without a history of CMV retinitis [32].

CMV specific immune responses — Although ART clearly leads to restoration of immune protection against further progression of CMV retinitis in nearly all CMV retinitis patients who respond to potent antiretroviral therapy [24,33,34], it is not clear whether ART leads to complete restoration of CMV-specific CD4+ and CD8+ T cell responses [35-38].

●As an example, in one longitudinal study of a CMV-specific CD8+ interferon gamma cytokine flow cytometry assay, immune responses in 10 patients with active CMV retinitis were compared to 20 patients who had a history of CMV retinitis and who successfully discontinued maintenance therapy [35]. CD8+ T cell responses were demonstrated in only 3 of 10 patients with active CMV retinitis compared to all 20 patients with a past history of CMV, suggesting full restoration of this critical CMV-specific T cell response.

●In an observational study of 87 patients with CD4 T counts less than 50 cells, positive baseline CMV-specific interferon gamma responses identified by ELISPOT (enzyme-linked immunospot) assay, were associated with delayed development of CMV viremia, end-organ disease, and death [36]. Factors associated with positive ELISPOT results were higher CD4 T cell counts, lower HIV ribonucleic acid (RNA) levels, and longer duration of ART. However, reconstitution of CMV-specific CD4+ and CD8+ T cell responses (as measured by flow cytometry) were not observed during the study.

●Another study identified three CMV-specific T cell parameters that discriminated between patients with active CMV retinitis and those who had full clinical recovery [39]. However, when these parameters were examined in a large, longitudinal study, they were not useful in predicting risk of developing CMV retinitis in patients with AIDS, possibly because the interval between the decrease in critical CMV-specific T cell subsets and the onset of retinitis was very short [40].

PATHOGENESIS — Many studies support the hypothesis that CMV retinitis results from hematogenous spread of CMV to the eye. Studies in transplant recipients and patients with AIDS indicate that CD4-dependent cytotoxic T lymphocyte activity of CMV antigen-specific CD8+ T cells is critical for preventing CMV replication and end-organ disease, and that impaired CD4 cell function or number is the key immune deficit that permits uncontrolled CMV replication [35,41,42].

Although most cases of CMV retinitis occur in patients with a CD4 count <50 cells/microL, patients may be predisposed before such severe CD4 cell depletion as illustrated below:

●In a longitudinal, prospective study, patients with AIDS who subsequently developed CMV retinitis had lower T-cell proliferative responses (in an assay that primarily measured CD4+ T cell proliferation) to CMV both early and late in disease, compared to patients who did not develop retinitis [43]. Genetic factors may contribute to this predisposition since low responses to CMV were more common in those with HLA B44 and DR7.

●A longitudinal study analyzed the dynamics of CMV-specific CD8+ and CD4+ T cell responses in parallel with CMV deoxyribonucleic acid (DNA) in 19 patients with HIV, 10 of whom had progression to CMV end-organ disease [44]. In individuals progressing to end-organ disease, CMV-specific IFN-gamma producing CD4+ T cells disappeared during the year before onset of clinical disease. This decline was accompanied by a sharp increase in CMV DNA before symptom onset.

●There is also evidence that higher proportions of regulatory T cells and of CMV-specific T-cell responses, which are characteristic of regulatory T cells, are associated with an increased risk of AIDS-related CMV end-organ disease [45].

In addition, there may be other genetic predispositions to developing CMV retinitis. For example, CMV contains a human interleukin-10 (IL-10) homolog in its genome to evade host immune reactions. Variants of the human IL-10 receptor may influence susceptibility to developing CMV retinitis in patients with AIDS [46].

PATHOLOGY — CMV retinitis is characterized histologically by full-thickness retinal necrosis and edema that is subsequently replaced by thin, atrophic scar tissue. This scar tissue is susceptible to tearing, which can lead to subsequent retinal detachment [47]. Without antiviral treatment or immune reconstitution, the retinal lesions enlarge centrifugally. The portions of the retina destroyed by CMV do not regenerate functionally. Thus, the goal of therapy for CMV retinitis is to prevent further retinal necrosis and loss of vision.

RISK FACTORS

CMV viremia — The presence of CMV virus in blood (as measured by culture, CMV DNA amplification, or antigen detection) has been studied as a risk factor for the development of CMV retinitis in patients with AIDS with varying results.

Several studies initiated before 1996 suggested a close association between CMV viremia and risk of CMV disease and mortality:

●One early study demonstrated that CMV DNA load was an independent marker of CMV disease and survival and was more predictive than HIV-1 RNA [48]. In addition, patients who attained CMV viral suppression with pre-emptive oral ganciclovir therapy had a significantly lower risk of developing CMV disease and higher rates of survival.

●In a large study of 619 AIDS patients, a positive plasma CMV DNA PCR was associated with a 2.5-fold increased risk of death [49]. Furthermore, each log(10) increase in baseline CMV DNA load was associated with a threefold increase in CMV disease and a twofold increase in mortality. However, 14 percent of individuals without detectable plasma CMV DNA at entry developed CMV end-organ disease as well.

However, the rate of CMV end-organ disease is lower in patients receiving combination ART. As an example, a randomized, placebo-controlled trial was performed in 338 patients with advanced AIDS, most of whom were taking ART [50]. Patients had serial measurements of CMV DNA by PCR and indirect ophthalmoscopy every eight weeks. Those with onset of CMV viremia were randomly assigned to either induction or maintenance doses of valganciclovir or placebo. The following results were reported:

●Sixty-eight (20 percent) developed viremia, of whom 47 entered the treatment phase of the study.

●There was no significant difference in rates of CMV end-organ disease or death between treatment arms.

In addition to the lack of benefit of pre-emptive anti-CMV therapy, this study highlights the much lower prevalence of CMV disease in patients taking modern ART regimens, compared to rates of 50 percent that were previously documented.

Iatrogenic risk factors — Iatrogenic risk factors (corticosteroids use, chemotherapy, radiotherapy and blood transfusions) for CMV retinitis were evaluated in a case-control study of 120 patients with CMV retinitis and 159 control patients, all of whom had AIDS and a CD4 T-cell <50 cells/microL [51]. Among the risk factors studied, only corticosteroid use was predictive of CMV retinitis (odds ratio 6.41, 95 percent CI 2.35-17.51).

CLINICAL MANIFESTATIONS — CMV retinitis can cause blurring or loss of central vision, scotomata ("blind spots"), floaters, or photopsia ("flashing lights"), depending upon the anatomic site of retinal destruction and whether or not retinal detachment has occurred [47]. A complaint of floaters or photopsia is the single most powerful symptomatic predictor of CMV retinitis in an AIDS patient [52] and should always be evaluated with dilated ophthalmoscopy. Lesions close to or involving the fovea or optic nerve are particularly likely to cause serious visual impairment. Acute loss of vision can occur if retinitis leads to retinal detachment.

CMV retinitis usually occurs as unilateral disease, but in the absence of therapy, involvement of the contralateral eye will often occur.

COMPLICATIONS — Retinal detachment is one of the major causes of vision loss in patients with CMV retinitis. Although the retina can be reattached anatomically by surgery, postoperative visual acuity is almost never as good as it was before detachment occurred. Peripheral (ie, anterior) retinal lesions underlie the vitreous base, where the vitreous body is normally adherent to the retina. Thus, large peripheral lesions are associated with an increased risk of retinal detachment.

In addition, some patients experiencing the immune reconstitution syndrome have developed a number of other ocular complications, including anterior uveitis, vitritis, and cystoid macular edema [33]. (See "Immune reconstitution inflammatory syndrome" and 'CMV immune recovery uveitis' below.)

DIAGNOSIS — CMV retinitis is generally diagnosed by an experienced ophthalmologist on the basis of characteristic retinal changes [53]. Indirect ophthalmoscopy reveals yellow-white retinal lesions with indistinct margins, sometimes with a granular appearance, often located close to retinal vessels and associated with hemorrhage. In the absence of antiretroviral therapy, CMV retinitis is associated with little inflammation of the vitreous; retinitis invariably progresses without treatment, usually within 10 to 21 days after presentation [53]. In resource-limited settings, ophthalmologists may be relatively inaccessible, and point-of-care indirect ophthalmoscopy by a trained nonophthalmologist may increase detection of retinitis up to 10-fold [20].

Lesions can be described as "fulminant and edematous" versus "indolent and granular" based on several factors, including the degree of retinal opacity (whitening), retinal hemorrhage, and lesion shape and location [54]. One retrospective observational study of 100 AIDS patients with untreated CMV retinitis suggested that lesion opacity may be a surrogate of disease severity [54]. The intensity of the white opaque borders is thought to represent virus activity [55].

Careful ophthalmologic exam is also important in distinguishing CMV retinitis from other retinal lesions:

●Small lesions may be difficult to differentiate from benign cotton wool spots; as a result, serial funduscopic examinations are sometimes required to make the diagnosis. The rate of enlargement of CMV lesions toward the fovea is slow but gradual. It is therefore safe to perform frequent examinations to confirm uncertain diagnoses before initiating therapy.

●CMV retinitis should be distinguished from progressive ocular retinal necrosis (PORN), a more aggressive retinitis typically caused by varicella zoster virus (VZV), or less commonly herpes simplex virus (HSV), which occurs primarily in patients with advanced HIV (CD4 <100 cells/microL). Very rarely, CMV has been implicated in PORN [56,57], and cases of PORN have occurred in patients without HIV [58,59]. PORN initially presents with multifocal, necrotizing lesions in the peripheral retina and progresses more rapidly compared with CMV retinitis [60]. In contrast to CMV retinitis, which typically involves the retinal vasculature, PORN typically spares retinal vessels. PORN lesions often rapidly coalesce, cause full thickness retinal necrosis, and lead to retinal detachment. For cases in which the clinical differentiation between CMV retinitis and PORN is not obvious, an aqueous or vitreous sample submitted for CMV, VZV, and HSV polymerase chain reaction (PCR) can be helpful for clarifying the diagnosis [61].

●The clinical syndrome of immune recovery uveitis may present with similar symptoms as the initial episode of CMV retinitis, but can be distinguished by a full ophthalmologic examination. (See 'CMV immune recovery uveitis' below.)

CMV viremia detected by PCR, antigen assays, or blood culture are not used to make a diagnosis of CMV retinitis or any other CMV end-organ disease in patients with HIV given the poor sensitivity and specificity of these tests for determining end-organ disease. As an example, in a study of patients with advanced AIDS and CMV viremia detected by PCR, fewer than 50 percent developed CMV end-organ disease at one year despite receiving no anti-CMV therapy [49]. Conversely, using the above methods for viral detection, CMV viremia is detected in less than half of patients with active retinitis [62,63].

Similarly, the presence of CMV antibodies is typically not useful in diagnosing CMV retinitis [53]. A negative IgG CMV antibody indicates that CMV is unlikely to be the etiology of retinitis. However, on rare occasion a patient with advanced HIV and prior CMV infection may serorevert from antibody-positive to antibody-negative. Thus, a negative CMV IgG antibody significantly lowers the diagnostic possibility of CMV, but does not completely eliminate it from consideration.

CMV IMMUNE RECOVERY UVEITIS — After an initial period of treatment with anti-CMV therapy and antiretroviral therapy (ART), patients may develop significant intraocular inflammation secondary to immune recovery. This entity is known as immune recovery uveitis (IRU) and can lead to significant ocular morbidity [1,29,33,64-66]. Complications of IRU accounted for approximately 50 percent of incident vision loss among patients with longstanding CMV retinitis and immune recovery in a study published in 2006 [67]. Anecdotally, IRU has rarely been diagnosed over the last decade.

Uveitis is a general term that refers to inflammation in the eye; vitritis refers to inflammation within the vitreous cavity and is a subset of uveitis. Immune recovery uveitis is associated with vitreous inflammation with or without cystoid macular edema, epiretinal membrane, or retinal neovascularization in patients with ART-mediated immune recovery and inactive CMV retinitis [1,68-70]. Although some patients develop transient vitritis soon after initiating ART and quickly recover normal visual function, IRU that leads to macular edema can often be associated with a significant decline in visual acuity despite successful treatment of CMV retinitis [29,70-72].

The pathogenesis of IRU is not well understood, but may be related to T cell-mediated immune reconstitution to latent CMV intraocular antigens [33,64,70,73] (see "Immune reconstitution inflammatory syndrome"). Symptoms include floaters, blurred vision, or photophobia. Patients may also develop other inflammatory complications such as cataract, glaucoma, and vitreous hemorrhage; neovascularization can occur as a late complication [64,69,74,75]. In a study of 54 patients with CMV retinitis conducted early in the modern ART era, the onset of IRU occurred within 2 to 84 weeks (median 20 weeks) after an improvement of CD4 cell counts [65].

In a subsequent study of 374 patients with AIDS and CMV retinitis affecting 539 eyes, 36 patients (9.6 percent) developed IRU involving 50 eyes [29]. Risk factors included prior CMV involvement of greater than 25 percent of the retina, involvement of the posterior pole of the eye, or treatment with intravitreal cidofovir. No patient with IRU was observed to have active retinitis or detectable CMV DNA in peripheral blood. The extent of prior CMV retinitis and the use of either systemic or intravitreal cidofovir has been identified as a potential cofactor in IRU in other studies as well [65,70,76,77].

Any patient with a history of immune recovery, quiescent CMV retinitis, and new visual symptoms, should be referred promptly for ophthalmic examination to evaluate for CMV progression, relapse, or immune recovery uveitis. On ophthalmologic examination, IRU is characterized by inflammation in the anterior chamber and vitreous cavity, which is best diagnosed with a combination of slit lamp examination and indirect ophthalmoscopy.

The treatment of IRU is discussed elsewhere. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV".)

SUMMARY AND RECOMMENDATIONS

●Cytomegalovirus (CMV) retinitis is the most common serious ocular complication of AIDS. Most disease is related to reactivation of latent infection. (See 'Introduction' above.)

●Risk factors for CMV retinitis include a CD4 count <50 cells/microL, history of prior opportunistic infection, high HIV RNA level, and CMV viremia.

●The introduction of potent combination antiretroviral therapy (ART) regimens has been associated with a decreased incidence of CMV retinitis, lower rates of ocular complications, and improved survival after diagnosis. (See 'CMV in the era of potent combination ART' above.)

●CMV retinitis can cause blurring or loss of central vision, scotomata ("blind spots"), floaters, or photopsia ("flashing lights"). Complications include retinal detachment with complete visual loss. (See 'Clinical manifestations' above.)

●CMV retinitis is generally diagnosed by an experienced ophthalmologist based on characteristic retinal changes. Indirect ophthalmoscopy reveals yellow-white retinal lesions with indistinct margins, sometimes with a granular appearance, often located close to retinal vessels and associated with hemorrhage. (See 'Diagnosis' above.)

●Testing for CMV viremia by DNA PCR, blood antigen, or blood culture is not helpful diagnostically. These assays have poor sensitivity and specificity for determining CMV end-organ disease and should not be used in clinical decision making when patients with AIDS are suspected of having CMV retinitis. (See 'Diagnosis' above.)

●A positive CMV antibody is not helpful diagnostically in the acute setting; a negative CMV antibody lowers the diagnostic possibility but does not eliminate CMV infection from consideration. (See 'Diagnosis' above.)

●After an initial period of treatment with anti-CMV therapy and ART, patients may present with visual blurring, floaters, or decreased visual acuity. If this occurs, the patient should be evaluated by an ophthalmologist to determine if these symptoms are related to CMV progression, relapse, or an immune reconstitution inflammatory syndrome, since their clinical management and treatment will differ. (See 'CMV in the era of potent combination ART' above and 'CMV immune recovery uveitis' above and "Treatment of AIDS-related cytomegalovirus retinitis".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.